WO2024075813A1 - Synthèse de polypeptides à l'aide d'un composé de dicétopipérazine - Google Patents

Synthèse de polypeptides à l'aide d'un composé de dicétopipérazine Download PDF

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WO2024075813A1
WO2024075813A1 PCT/JP2023/036352 JP2023036352W WO2024075813A1 WO 2024075813 A1 WO2024075813 A1 WO 2024075813A1 JP 2023036352 W JP2023036352 W JP 2023036352W WO 2024075813 A1 WO2024075813 A1 WO 2024075813A1
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formula
general formula
compound
pge
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尚 山本
勝 満田
倫弘 服部
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学校法人中部大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids

Definitions

  • the present invention relates to a novel diketopiperazine compound and a method for producing the same, as well as a method for producing a polypeptide using the novel diketopiperazine compound.
  • polypeptides have been considered important as an innovative drug discovery modality for next-generation pharmaceuticals. Therefore, there is an urgent need to develop technology and establish a supply system to quickly and cheaply synthesize polypeptides with specific sequences and supply them to drug discovery and medical facilities.
  • polypeptides are synthesized by organic synthetic chemistry techniques, using methods known as liquid phase synthesis or solid phase synthesis.
  • amino acids with protected amino groups are used as raw materials, and after activating the protected amino acids, they are condensed with another amino acid or a peptide compound, the protecting group of the amino group is removed, and condensation with the next amino acid is initiated.
  • This is an extremely complicated method of extending the peptide chain one by one (Non-Patent Documents 1, 2, 3, 4).
  • this series of processes includes operations such as acid treatment, base treatment, solvent extraction, and solvent washing, and the large amount of waste generated during this process not only increases production costs, but also poses a major problem from the perspective of protecting the global environment.
  • Non-Patent Documents 7, 8, 9 disclose a process for breeding a host that produces the target polypeptide and for obtaining the pure target product from the large amount of biological impurities contained in the culture solution.
  • Patent Document 1 a method of amidating a carboxylic acid/ester compound having a hydroxy group at the ⁇ -position in the presence of a specific metal catalyst
  • Patent Document 2 a method of using a hydroxyamino/imino compound as an amino acid precursor, amidating this in the presence of a specific metal catalyst, and then reducing it in the presence of a specific metal catalyst
  • Patent Document 3 a method of amidating a carboxylic acid/ester compound in the presence of a specific metal catalyst
  • Patent Document 4 a technique for synthesizing peptides consisting of various amino acid residues with high efficiency and high selectivity by amidating the carboxyl group of an N-terminal protected amino acid/peptide with the amino group of a C-terminal protected amino acid/peptide in the presence of a specific silylating agent (and a Lewis acid catalyst optionally used in combination), followed by deprotection
  • Patent Document 4 a technique for synthesizing peptides consisting of various amino acid residues with high efficiency and high selectivity by amidating the carboxyl group of an N-terminal protected or unprotected amino acid/peptide with the amino group of a C-terminal protected or unprotected amino acid/peptide in the presence of a specific silylating agent, followed by deprotection
  • Patent Documents 5 and 6 a technique for performing an amidation reaction using a Brönsted acid as a catalyst
  • Patent Document 7 a novel silane-containing condensed ring dipeptide compound and
  • the present invention was made in consideration of the above background, and its purpose is to provide a method for quickly and easily synthesizing a polypeptide having any sequence.
  • the gist of the present invention relates to, for example, the following.
  • [Item 1] General formula (1): (In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 each independently represent a hydrogen atom, an unsubstituted or substituted hydrocarbon group, or an unsubstituted or substituted heterocyclic group. However, R 1 and R 2 , R 1 and R 5 , R 2 and R 5 , and/or R 3 and R 4 may be linked to form a ring.
  • PGE represents an electron-withdrawing protecting group.
  • PGE represents an electron-withdrawing protecting group.
  • a method for producing a diketopiperazine compound represented by the following formula: (a) General formula (2): (In the formula, R 1 , R 2 , R 3 , and R 4 have the same definitions as in formula (1′), and PGA represents an alkyl-type protecting group.)
  • a diketopiperazine compound having two different protecting groups PGE and PGA introduced therein is obtained, (b) removing only the alkyl-type protecting group PGA from the compound of formula (3) obtained in the step (a).
  • the manufacturing method further comprises: (c) General formula (4): (In the formula, R 1 , R 2 , R 3 , and R 4 are defined the same as in formula (1′), PGA is defined the same as in formula (2), R 6 is independent of R 1 to R 4 and represents a hydrogen atom, an unsubstituted or substituted hydrocarbon group, or an unsubstituted or substituted heterocyclic group, and R 7 represents hydrogen or an amino-protecting group which can be removed under acidic conditions.)
  • the method includes treating a dipeptide compound represented by the following general formula (3) under acidic conditions to obtain the compound represented by the following general formula (3): Item 7.
  • the manufacturing method further comprises: (d) General formula (5): (In the formula, R 1 and R 2 have the same definition as in formula (1'), PGA has the same definition as in formula (2), and R 7 has the same definition as in formula (4).) and an amino acid protected with an alkyl-type substituent represented by general formula (6): (In the formula, R3 and R4 have the same definition as in formula (1'), and R6 has the same definition as in formula (4).) and an amino acid ester represented by the general formula (4) to obtain a compound represented by the general formula (4), Item 8.
  • step (d) The method according to Item 7, wherein the compound of formula (4) obtained in step (d) is used as a raw material in step (c).
  • step (d) The method according to any one of Items 6 to 8, wherein PGA is a benzyl group or a substituted benzyl group.
  • step 10 The method according to any one of Items 6 to 9, wherein PGE is a tert-butoxycarbonyl group.
  • item 11 The method according to any one of items 7 to 10, wherein R 6 is a methyl group or an ethyl group.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 each independently represent a hydrogen atom, an unsubstituted or substituted hydrocarbon group, or an unsubstituted or substituted heterocyclic group.
  • R 1 and R 2 , R 1 and R 5 , R 2 and R 5 , R 3 and R 4 , R 8 and R 9 , and/or R 10 and R 11 may be linked to form a ring.
  • X represents a hydroxyl group, an alkoxyl group, an alkylthio group, an amino group, or a substituted amino group.
  • n represents 0 or 1
  • p represents an integer of 2 or more.
  • R 1 , R 2 , R 3 , R 4 , and R 5 each may be 2 or more. and when m is 2 or more, each of two or more R 8 , R 9 , and R 13 may be the same or different.
  • PGE represents an electron-withdrawing protecting group.
  • novel diketopiperazine compounds of the present invention can be used as versatile building blocks for polypeptide synthesis. This makes it possible to rapidly and easily synthesize polypeptides with any sequence.
  • amino acid refers to a compound having a carboxyl group and an amino group.
  • the type of amino acid is not particularly limited.
  • it may be D-form, L-form, or racemic.
  • it may be any of ⁇ -amino acid, ⁇ -amino acid, ⁇ -amino acid, ⁇ -amino acid, ⁇ -amino acid, etc.
  • amino acids include, but are not limited to, natural amino acids that constitute proteins, and specific examples include valine, leucine, isoleucine, alanine, arginine, glutamine, lysine, aspartic acid, glutamic acid, proline, cysteine, threonine, methionine, histidine, phenylalanine, tyrosine, tryptophan, asparagine, glycine, serine, etc.
  • peptide refers to a compound in which multiple amino acids are linked via peptide bonds.
  • the multiple amino acid units constituting a peptide may be the same type of amino acid unit, or may be two or more different types of amino acid units.
  • the number of amino acids constituting a peptide is not particularly limited as long as it is two or more. Examples include 2 (also called “dipeptides”), 3 (also called “tripeptides”), 4 (also called “tetrapeptides”), 5 (also called “pentapeptides”), 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 100, or more.
  • polypeptide may refer to a peptide that is tripeptide or more.
  • an "amino group” refers to a functional group represented by the formula -NH 2 , -NRH, or -NRR' (wherein R and R' each represent a substituent) obtained by removing hydrogen from ammonia, a primary amine, or a secondary amine, respectively.
  • the hydrocarbon group may be aliphatic or aromatic.
  • the aliphatic hydrocarbon group may be linear or cyclic.
  • the linear hydrocarbon group may be linear or branched.
  • the cyclic hydrocarbon group may be monocyclic, bridged, or spirocyclic.
  • the hydrocarbon group may be saturated or unsaturated, in other words, may contain one or more carbon-carbon double bonds and/or triple bonds. That is, the concept of the hydrocarbon group includes alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, aryl groups, and the like.
  • one or more hydrogen atoms of the hydrocarbon group may be replaced with any substituent, and one or more carbon atoms of the hydrocarbon group may be replaced with any heteroatom depending on the valence.
  • hydrocarbon oxy group refers to a group in which a hydrocarbon group as defined above is linked to one bond of an oxy group (-O-).
  • a heterocyclic group may be saturated or unsaturated, in other words, may contain one or more carbon-carbon double bonds and/or triple bonds.
  • a heterocyclic group may be monocyclic, bridged, or spirocyclic.
  • the heteroatoms contained in the heterocyclic rings of a heterocyclic group are not limited, but examples include nitrogen, oxygen, sulfur, phosphorus, silicon, etc.
  • heterocyclic oxy group refers to a group in which a heterocyclic group as defined above is linked to one bond of an oxy group (-O-).
  • substituteduents refer to any substituent, each independently and unless otherwise specified, without any particular limitation as long as the amidation step in the production method of the present invention proceeds.
  • alkyl group include, but are not limited to, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, a thiol group, a sulfonic acid group, an amino group, an amido group, an imino group, an imido group, a hydrocarbon group, a heterocyclic group, a hydrocarbonoxy group, a hydrocarboncarbonyl group (acyl group), a hydrocarbonoxycarbonyl group, a hydrocarboncarbonyloxy group, a hydrocarbon-substituted amino group, a hydrocarbon-substituted aminocarbonyl group, a hydrocarboncarbonyl-substituted amino group, a hydrocarbon-substituted thiol group, a hydrocarbons
  • amino acids and their residues may be represented by three-letter abbreviations well known to those skilled in the art.
  • the three-letter abbreviations of the main amino acids used in this disclosure are shown in the following table.
  • ⁇ -homo amino acids and their residues may be represented by adding "Ho" before the three-letter abbreviation of the corresponding ⁇ -amino acid.
  • protecting group refers to a functional group that can be introduced onto the nitrogen atom of an amino or amide group under specific reaction conditions and can be removed under specific reaction conditions. Representative protecting groups are described in detail in several textbooks, such as Peter G. M. Wuts, Greene's Protective Groups in Organic Synthesis, 5th Edition, Wiley, 2014.
  • alkyl-type protecting group refers to a hydrocarbon group that can be easily attached to and detached from the nitrogen atom of an amino group or an amide group. Examples include an unsubstituted or substituted benzyl group, an unsubstituted or substituted allyl group, etc.
  • the term "electron-withdrawing protecting group” refers to a protecting group that acts as a protecting group for an amino group or an amide group, and that attracts electrons on the nitrogen atom toward the protecting group.
  • examples include acyl groups, alkyloxycarbonyl groups, alkylsulfonyl groups, and arylsulfonyl groups.
  • One aspect of the present invention relates to a novel diketopiperazine compound represented by general formula (1) (hereinafter referred to as "the diketopiperazine compound of the present invention” or “the compound of the present invention” as appropriate).
  • R 1 , R 2 , R 3 , R 4 , and R 5 each independently represent a hydrogen atom, a hydrocarbon group which is unsubstituted or substituted with one or more substituents, or a heterocyclic group which is unsubstituted or substituted with one or more substituents.
  • R 1 , R 2 , R 3 , R 4 , and R 5 include, but are not limited to, a hydrogen atom, a methyl group, an ethyl group, an allyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a phenyl group, a benzyl group, a 4-methoxybenzyl group, a 2,4-dimethoxybenzyl group, a 3,4-dimethoxybenzyl group, a 4-hydroxybenzyl group, a 2,4-hydroxybenzyl group, a 3,4-hydroxybenzyl group, a hydroxymethyl group, a 1-hydroxypropyl group, an indole group, a mercaptomethyl group, a methylthioethyl group, an aminobutyl group, a methoxycarbonylmethyl group, a methoxycarbonylethyl group, an imidazolylmethyl group, an amidomethyl
  • R1 and R2 , R1 and R5 , R2 and R5 , and/or R3 and R4 may be linked together to form a ring (e.g., a cyclic aliphatic hydrocarbon group, an aromatic hydrocarbon group, or a heterocyclic group). These rings may be further substituted with one or more substituents. When these rings have a substituent, the type of the substituent is as described above. When these rings have two or more substituents, they may be the same or different.
  • R 1 to R 5 are each a hydrocarbon group or a heterocyclic group
  • a linking group may be present between the hydrocarbon group or heterocyclic group and the carbon atom or nitrogen atom to which it is bonded.
  • Such linking groups are not limited, but may each be independently selected from the structures shown below (note that in the chemical formula below, each A independently represents a hydrocarbon group or a heterocyclic group of R 1 to R 5. When there are two A in the same group, they may be the same or different).
  • PGE represents an electron-withdrawing protecting group.
  • Specific examples include carbamate-type protecting groups such as tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, and benzyloxycarbonyl groups, sulfonyl-type protecting groups such as methanesulfonyl, benzenesulfonyl, and p-benzenesulfonyl groups, and bulky acyl groups such as benzoyl and pivaloyl groups.
  • the electron-withdrawing protecting group a carbamate-type protecting group is preferred, and a tert-butoxycarbonyl group is more preferred.
  • the diketopiperazine compounds of the present invention can be used as versatile building blocks for polypeptide synthesis. This makes it possible to rapidly and easily synthesize polypeptides having any sequence. A method for producing such polypeptides will be described later.
  • the method for producing the diketopiperazine compound of the present invention is not limited, and it can be produced by any method.
  • the compound in which R 5 of general formula (1) is a hydrogen atom that is, the diketopiperazine compound represented by the following general formula (1')
  • the present invention also provides a method for producing the diketopiperazine compound of general formula (1').
  • R1 , R2 , R3 , R4 , and PGE are the same as those in general formula (1).
  • R1 and R2 , and/or R3 and R4 may be linked to form a ring (e.g., a cyclic aliphatic hydrocarbon group, an aromatic hydrocarbon group, or a heterocyclic group), and such a ring may further have one or more substituents.
  • the diketopiperazine compound of formula (1') is preferably produced by the synthesis route shown in Scheme 1 below.
  • Such a production method for the diketopiperazine compound of formula (1') (hereinafter referred to as the "production method for the diketopiperazine compound of the present invention” or the “production method for compound (1') of the present invention” as appropriate) also constitutes one aspect of the present invention.
  • the method for producing a diketopiperazine compound of the present invention may include at least step (a) of obtaining a compound of general formula (3) by adding an electron-withdrawing protecting group PGE to a compound of general formula (2), and step (b) of obtaining a compound of general formula (1') by removing an alkyl-type protecting group PGA from a compound of general formula (3).
  • Step (c) of synthesizing a compound of general formula (2) from a compound of general formula (4), and step (d) of synthesizing a compound of general formula (4) by reacting a compound of general formula (5) with a compound of general formula (6) are not essential but are optional. In light of this, steps (a), (b), (c), and (d) will be described below in this order.
  • a diketopiperazine compound represented by the following general formula (2) in which one nitrogen atom in a 6-membered ring is protected with an alkyl-type protecting group
  • a diketopiperazine compound represented by the following general formula (3) in which two different protecting groups PGE and PGA have been introduced, by protecting the other unprotected nitrogen atom in the 6-membered ring with an electron-withdrawing protecting group.
  • R 1 , R 2 , R 3 , and R 4 have the same definitions as in general formulas (1) and (1').
  • R 1 and R 2 and/or R 3 and R 4 may be linked to form a ring (e.g., a cyclic aliphatic hydrocarbon group, an aromatic hydrocarbon group, or a heterocyclic group), and such a ring may further have one or more substituents.
  • PGA represents an alkyl-type protecting group.
  • examples include a benzyl group, a substituted benzyl group, an allyl group, and a substituted allyl group. More specifically, examples include a benzyl group, a 4-methoxybenzyl group, a 3,4-dimethoxybenzyl group, and a 2,4-dimethoxybenzyl group. Of these, the 4-methoxybenzyl group is preferred.
  • PGE represents an electron-withdrawing protecting group. Details are as explained for general formula (1).
  • step (a) the reaction conditions for protecting the nitrogen atom in the six-membered ring with an electron-withdrawing protecting group are not particularly limited and can be selected appropriately.
  • the conditions for introducing individual protecting groups are widely known to those skilled in the art and are also described in detail in the aforementioned textbook (Greene's Protective Groups in Organic Synthesis).
  • reaction conditions for removing the electron-withdrawing protecting group in step (b) are not particularly limited and can be selected appropriately.
  • the reaction conditions for removing each protecting group are widely known to those skilled in the art and are described in detail in the aforementioned textbook (Greene's Protective Groups in Organic Synthesis).
  • the compound of general formula (3) used in step (a) may be an existing compound or may be synthesized.
  • the method for synthesizing the compound of general formula (3) is not particularly limited, but it is preferable to synthesize the compound by treating a dipeptide compound represented by the following general formula (4) under acidic conditions.
  • a step (c) of synthesizing a dipeptide compound of general formula (3) by such a method may be provided before step (a) in the method for producing a diketopiperazine compound of the present invention.
  • R 1 , R 2 , R 3 , and R 4 have the same definitions as in general formulas (1) and (1').
  • R 1 and R 2 and/or R 3 and R 4 may be linked to form a ring (e.g., a cyclic aliphatic hydrocarbon group, an aromatic hydrocarbon group, or a heterocyclic group), and such a ring may further have one or more substituents.
  • PGA represents an alkyl-type protecting group. Details are as explained for general formulas (2) and (3).
  • R6 represents, independently of R1 to R4 , a hydrogen atom, an unsubstituted or substituted hydrocarbon group, or an unsubstituted or substituted heterocyclic group.
  • Preferred examples of R6 include, but are not limited to, a methyl group or an ethyl group.
  • R7 represents a hydrogen atom or an amino-protecting group that is removable under acidic conditions.
  • Specific examples include a hydrogen atom, a methoxycarbonyl group, and a tert-butoxycarbonyl group. Of these, a hydrogen atom or a tert-butoxycarbonyl group is preferable.
  • Bronsted acids and Lewis acids can be used as the acidic conditions for the reaction in step (c).
  • Bronsted acids are preferred. Specific examples include formic acid, acetic acid, propionic acid, benzoic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid, hydrochloric acid, sulfuric acid, and nitric acid.
  • carboxylic acids such as formic acid and acetic acid are preferred.
  • the amount of acid used in the reaction of step (c) is 0.1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to the dipeptide compound of general formula (4).
  • the reaction solvent used in this reaction can be an alcohol solvent such as methanol or ethanol, a hydrocarbon solvent such as toluene, an ether solvent such as tetrahydrofuran, an ester solvent such as ethyl acetate, a nitrogen-containing solvent such as acetonitrile, an aprotic polar solvent such as dimethyl sulfoxide, a halogenated solvent such as dichloromethane, or a mixture of these.
  • an alcohol solvent such as methanol or ethanol
  • a hydrocarbon solvent such as toluene
  • an ether solvent such as tetrahydrofuran
  • an ester solvent such as ethyl acetate
  • a nitrogen-containing solvent such as acetonitrile
  • an aprotic polar solvent such as dimethyl sulfoxide
  • a halogenated solvent such as dichloromethane, or a mixture of these.
  • the reaction proceeds at temperatures between 20 and 120°C, but may be heated further to increase the rate.
  • the reaction time is 1 to 12 hours, and if the amount of acid used and the reaction temperature are appropriately selected, the reaction will be completed within 1 to 5 hours.
  • the dipeptide compound of general formula (4) used in step (c) may be an existing compound or may be synthesized.
  • the method for synthesizing the dipeptide compound of general formula (4) is not particularly limited, but it is preferable to synthesize the compound by condensing an amino acid protected with an alkyl-type substituent represented by the following general formula (5) with an amino acid ester represented by the following general formula (6).
  • a step (d) of synthesizing the dipeptide compound of general formula (4) by such a method may be provided before step (c) in the method for producing a diketopiperazine compound of the present invention.
  • R 1 , R 2 , R 3 , and R 4 have the same definitions as in general formulas (1) and (1').
  • R 1 and R 2 and/or R 3 and R 4 may be linked to form a ring (e.g., a cyclic aliphatic hydrocarbon group, an aromatic hydrocarbon group, or a heterocyclic group), and such a ring may further have one or more substituents.
  • R6 and R7 have the same definitions as in formula (4).
  • PGA has the same definition as in general formula (2).
  • the type and conditions of the condensation reaction in step (d) are not particularly limited and can be selected as appropriate.
  • the synthesis can be performed using the reaction conditions of the method described in the literature (e.g., T. Hattori et al., J. Am. Chem. Soc., (2022), vol. 144, No. 4, pp. 1758-1765, etc.).
  • a conventional peptide synthesis reaction using a condensation agent and an activator can also be used.
  • the above-described method for producing a diketopiperazine compound of the present invention makes it possible to efficiently synthesize a diketopiperazine compound of the present invention having any structure composed of any natural or unnatural amino acid.
  • Another aspect of the present invention relates to a method for producing a polypeptide having a chain length of tetrapeptide or longer by using a diketopiperazine compound of the present invention as a building block (hereinafter appropriately referred to as "method for producing the polypeptide of the present invention").
  • the method for producing a polypeptide of the present invention uses a nitrogen nucleophile compound represented by general formula (8) and p types of diketopiperazine compounds of general formula (1) (the compounds of the present invention) to produce a polypeptide represented by general formula (7).
  • a nitrogen nucleophile compound represented by general formula (8) and p types of diketopiperazine compounds of general formula (1) (the compounds of the present invention) to produce a polypeptide represented by general formula (7).
  • R 1 , R 2 , R 3 , R 4 , R 5 and PGE have the same definitions as in general formula (1).
  • R 1 and R 2 , R 1 and R 5 , R 2 and R 5 , and/or R 3 and R 4 may be linked to form a ring (e.g., a cyclic aliphatic hydrocarbon group, an aromatic hydrocarbon group, or a heterocyclic group), and such a ring may further have one or more substituents.
  • R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 each independently represent a hydrogen atom, a hydrocarbon group which is unsubstituted or substituted with one or more substituents, or a heterocyclic group which is unsubstituted or substituted with one or more substituents.
  • R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 include, but are not limited to, a hydrogen atom, a methyl group, an ethyl group, an allyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a phenyl group, a benzyl group, a 4-methoxybenzyl group, a 2,4-dimethoxybenzyl group, a 3,4-dimethoxybenzyl group, a 4-hydroxybenzyl group, a 2,4-hydroxybenzyl group, a 3,4-hydroxybenzyl group, a hydroxymethyl group, a 1-hydroxypropyl group, an indole group, a mercaptomethyl group, a methylthioethyl group, an aminobutyl group, a methoxycarbonylmethyl group, a methoxycarbonylethyl group, an imidazolylmethyl group,
  • R8 and R9 , and/or R10 and R11 may be linked together to form a ring (e.g., a cyclic aliphatic hydrocarbon group, an aromatic hydrocarbon group, or a heterocyclic group). These rings may be further substituted with one or more substituents. When these rings have a substituent, the type of the substituent is as described above. When these rings have two or more substituents, they may be the same or different.
  • R 8 to R 13 are each a hydrocarbon group or a heterocyclic group
  • a linking group may be present between the hydrocarbon group or heterocyclic group and the carbon atom or nitrogen atom to which it is bonded.
  • Such linking groups are not limited, but may each be independently selected from the structures shown below (note that in the chemical formula below, each A independently represents a hydrocarbon group or heterocyclic group of R 1 to R 5. When there are two A in the same group, they may be the same or different).
  • X represents a hydroxyl group, an alkoxyl group, an alkylthio group, an amino group, or a substituted amino group having one or two substituents.
  • a substituted amino group the type of the substituent is as described above.
  • X include, but are not limited to, a hydroxyl group, a methoxy group, an ethoxy group, an isopropoxy group, a tert-butoxy group, a phenoxy group, a benzyloxy group, a methylthio group, an ethylthio group, a tert-butylthio group, a phenylthio group, an amino group, a methylamino group, a dimethylamino group, a benzylamino group, a dibenzylamino group, and a 4-methoxybenzylamino group.
  • m represents an integer of 0 or more, and n represents 0 or 1.
  • R8 , R9 , and R13 each of which is 2 or more, may be the same or different.
  • the m structural units (amino acid residues) in the parentheses with m in general formulas (7) and (8) may be the same or different from each other.
  • p represents an integer of 2 or more.
  • R 1 , R 2 , R 3 , R 4 , and R 5 each of which is 2 or more, may be the same or different.
  • the p structural units (dipeptide residues) in the parentheses with p in general formula (7) may be the same or different.
  • the method for producing the polypeptide of the present invention includes the following steps (x) and (y).
  • a nitrogen nucleophile compound represented by general formula (8) is used as a nitrogen nucleophile to react with a diketopiperazine compound represented by general formula (1) (the compound of the present invention) to open the lactam group containing a nitrogen atom to which the electron-withdrawing protecting group PGE of the compound of general formula (1) is bonded, and the resulting dipeptide is linked to the N-terminal amino group of the compound of general formula (8), thereby obtaining a reaction product (a compound represented by general formula (7') in the above scheme 2).
  • reaction conditions in step (x) are not particularly limited and can be selected arbitrarily.
  • hydrocarbon solvents such as toluene
  • ether solvents such as tetrahydrofuran
  • ester solvents such as ethyl acetate
  • nitrogen-containing solvents such as acetonitrile
  • aprotic polar solvents such as dimethylsulfoxide
  • halogenated solvents such as dichloromethane
  • step (x) can be carried out under mild, neutral conditions at 0 to 60°C, but the reaction may be accelerated, if necessary, by heating or adding a base catalyst.
  • a new diketopiperazine compound of general formula (1) the compound of the present invention
  • step (y) the reaction product obtained in step (y) from which the electron-withdrawing protecting group has been removed can be used as a new nitrogen nucleophile to react with a new diketopiperazine compound of general formula (1) (the compound of the present invention), a simple routine operation, i.e., step (y), can be repeatedly carried out. In this way, by repeating step (y) p-1 times, it is possible to obtain a polypeptide of general formula (7).
  • the total p kinds of diketopiperazine compounds of general formula (1) (compounds of the present invention) used in step (x) and p-1 times of step (y) may be the same or different.
  • the type and order of the diketopiperazine compounds of general formula (1) (compounds of the present invention) used it is possible to obtain a polypeptide of general formula (7) having any amino acid sequence.
  • the conditions for the deprotection reaction of the electron-withdrawing protecting group PGE are not particularly limited and can be selected appropriately.
  • the conditions for removing individual protecting groups are widely known to those skilled in the art and are also described in detail in the aforementioned textbook (Greene's Protective Groups in Organic Synthesis).
  • step (x) and/or step (y) may be performed under microwave irradiation.
  • the reaction rate may be accelerated.
  • the conditions are as follows.
  • a commercially available microwave generator for example, Discover SP Microwave Synthesizer from CEM
  • the power used for generating microwaves but it may be, for example, 100 to 1600 W.
  • the microwave irradiation time but it may be, for example, 0.5 to 12 hours.
  • steps (x) and (y) can be carried out consecutively in the same reaction solvent as exemplified above, but the reaction products obtained in each step can be isolated and purified by conventional methods before being used in the next step.
  • the polypeptide of general formula (7) obtained by the method for producing a polypeptide of the present invention may be subjected to various post-treatments.
  • the produced polypeptide of general formula (7) may be isolated and purified by conventional methods such as column chromatography and recrystallization.
  • the produced polypeptide of general formula (7) has an amino group and/or a carboxyl group protected by a protecting group or the like, it may be deprotected by the method described below.
  • the method for producing a polypeptide of the present invention using the diketopiperazine compound of the present invention described above differs from conventional peptide synthesis methods in that it allows two amino acids to be elongated at once in one step. Furthermore, it does not require specialized knowledge or experience specific to peptide chemistry and can be easily carried out. Furthermore, even in the case of peptide synthesis containing a non-natural amino acid that is known to be difficult to synthesize, synthesis of a polypeptide containing this can be easily carried out by using the diketopiperazine compound of the present invention that already contains this amino acid.
  • the present invention provides a completely new methodology for peptide synthesis that allows anyone to quickly obtain a desired polypeptide with simple routine operations.
  • diketopiperazine compounds of the present invention that are used as versatile building blocks, which are key raw materials in the method for producing the polypeptides of the present invention
  • diketopiperazine compounds composed of any natural or unnatural amino acid can be efficiently synthesized by using the method for producing diketopiperazine compounds of the present invention described above.
  • the present invention provides a new methodology for polypeptide synthesis, and it may be particularly preferable to carry out the method for producing the polypeptide of the present invention using a diketopiperazine compound of the present invention having a specific structure.
  • a polypeptide in which an unsubstituted or substituted hydrocarbon group is introduced as R 5 in general formula (7) can be produced.
  • a polypeptide in which an unsubstituted or substituted hydrocarbon group is introduced on the amide nitrogen instead of a hydrogen atom in R 5 is less susceptible to degradation by enzymes such as peptidase in vivo, and is therefore frequently used in partial structures aimed at improving the pharmacokinetics of peptide drugs.
  • a polypeptide in which R 1 and R 2 are not both hydrogen atoms and/or R 3 and R 4 are not both hydrogen atoms has the effect of increasing absorbability in the body, and is therefore frequently used in partial structures aimed at improving the bioavailability of peptide pharmaceuticals.
  • R 1 and R 2 are not both hydrogen atoms and/or R 3 and R 4 are not both hydrogen atoms
  • R 1 and R 2 are not both hydrogen atoms and/or R 3 and R 4 are not both hydrogen atoms
  • the method for producing a polypeptide of the present invention using the diketopiperazine compound of the present invention may be combined with other conventionally known amidation methods or peptide production methods to further extend the amino acid residues. In principle, this makes it possible to synthesize a polypeptide with any number of amino acid residues and any amino acid sequence.
  • Patent Document 3 2018/199147 (Patent Document 3) (4) International Publication No. 2019/208731 (Patent Document 4) (5) International Publication No. 2021/085635 (Patent Document 5) (6) International Publication No. 2021/085636 (Patent Document 6) (7) International Publication No. 2021/149814 (Patent Document 7) (8) International Publication No. 2022/190486 (Patent Document 8)
  • the present inventors have also disclosed a method for producing a polypeptide compound by an amide-forming reaction between an amino-protected lactam compound of a specific structure and an amino acid ester or peptide ester compound of a specific structure (W. Muramatsu et al., Chem. Sci., (2022), Vol. 13, pp. 6309-6315; Non-Patent Document 8 mentioned above), and have filed a separate prior patent application (International Patent Application PCT/JP2022/024418; unpublished at the time of filing this application).
  • the method for producing a polypeptide of the present invention can be carried out in appropriate combination with the amidation reaction and the method for producing a polypeptide described in the non-patent document and the prior patent application, and/or can be appropriately modified in consideration of the conditions of the amidation reaction and the method for producing a polypeptide described in these prior patent applications.
  • the descriptions in the non-patent document and the prior patent application are also incorporated herein in their entirety by reference.
  • Boc-Gly-Gly-Phe-OBzl 7a, 375 mg, 0.8 mmol was added to a dry 50 mL flask together with a magnetic stirring bar, and 4N HCl/1,4-dioxane (15 mL) was added under cooling at 0° C., followed by stirring at room temperature for 15 minutes. After confirming the completion of the reaction by TLC, the reaction was quenched with saturated aqueous sodium bicarbonate (20 mL).
  • reaction mixture was transferred to a separatory funnel and extracted three times with chloroform (30 mL).
  • the organic layer was then dried over anhydrous magnesium sulfate, and the residue obtained by concentrating the solvent was purified by flash silica gel column chromatography (0 to 10% MeOH in CHCl 3 ) to obtain H-Gly-Gly-Phe-OBzl (9a) in which the terminal amino group was deprotected as a colorless oil (160 mg, yield 54%).
  • a flame-dried 5.0 mL screw-cap vial containing a magnetic stir bar was charged with ⁇ -Me-N-AA1-OH of formula 1 (0.50 mmol), bis(1-imidazolyl)dimethylsilane (105 mg, 0.55 mmol), and dry dichloromethane (200 ⁇ L).
  • the reaction mixture was stirred vigorously at room temperature for 5 min, followed by addition of 1-(trimethylsilyl)imidazole (110.2 ⁇ L, 0.75 mmol), Ta(OEt) 5 (13 ⁇ L, 0.050 mmol), and H-L-AA2-OMe of formula 2 (1 mmol, 2 equiv.).
  • the vial was sealed under an argon atmosphere and removed from the glove box.
  • the reaction mixture was stirred vigorously at 60° C. for 24 h, after which the reaction mixture was purified by flash column chromatography (0-5% methanol in chloroform) to give cyclo(-L-AA1-Me-AA2-) of formula 3.
  • reaction mixture was transferred to a separatory funnel with chloroform (20 mL) and saturated aqueous ammonium chloride (NH 4 Cl) solution (15 mL) was added.
  • NH 4 Cl saturated aqueous ammonium chloride
  • the phases were separated and the aqueous phase was extracted with chloroform (2 ⁇ 20 mL).
  • the organic phase was washed with water (10 mL) and brine ( 10 mL), dried over sodium sulfate ( Na2SO4 ), filtered, and concentrated in vacuo using a rotary evaporator and water bath without heat.
  • the resulting crude product was purified by flash column chromatography (0-60% ethyl acetate in hexanes) to give the compound of formula 4.
  • Example 2a By using alanine (Me as R and R1 ) as AA1 and AA2, compounds of formula 3a and formula 4a below were obtained.
  • Example 2b By using alanine (-R is -Me) as AA1 and phenylalanine (-R 1 is -Me-Ph) as AA2, the compounds of the following formulae 3b and 4b were obtained.
  • H-Phe-OMe.HCl (15.0 mmol) and dry methanol (20 mL) were placed in a flame-dried 100 mL flask containing a magnetic stir bar under nitrogen and sealed with a rubber septum.
  • the reaction mixture was cooled to 0° C. and triethylamine (2 mL, 1 equiv.) was added via syringe and stirred at 0° C. for 5 min followed by 10 min at room temperature.
  • p-Methoxybenzaldehyde (2.2 mL, 1.2 equiv.) was then added via syringe to the reaction mixture and stirred at room temperature for 2 h before being cooled to 0° C.
  • the dipeptide of formula 3 PMB-NH-Phe-Leu-OMe (413 mg, 1.0 mmol) synthesized above, toluene and acetic acid (182 mg, 3 equiv.) were placed in a flame-dried 5.0 mL screw-cap vial containing a magnetic stir bar.
  • the reaction vial was sealed with a screw cap and vinyl tape, and the reaction mixture was stirred in a preheated oil bath at 120° C. for 2 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (5 mL).
  • reaction mixture was transferred to a separatory funnel with chloroform (15 mL) and saturated aqueous ammonium chloride (NH 4 Cl) solution (10 mL) was added.
  • NH 4 Cl saturated aqueous ammonium chloride
  • the phases were separated and the aqueous phase was extracted with chloroform (chloroform, 2 ⁇ 20 mL).
  • the organic phase was washed with water (10 mL) and brine (10 mL), dried over sodium sulfate (Na 2 SO 4 ), filtered, and concentrated in vacuo using a rotary evaporator and water bath without heat.
  • the resulting crude product was purified by flash column chromatography (0-20% ethyl acetate in hexanes) to give the compound of formula 4 as a sticky solid (yield 0.455 g, 94%).
  • the tripeptide of formula 3 obtained above (0.177 mg, 0.41 mmol) was placed in a 50 mL flask equipped with a magnetic stir bar and a rubber septum and cooled to 0° C. 10 mL of 4N hydrochloric acid in dioxane was added at 0° C. and the reaction mixture was allowed to stand at 0° C. for 15 min. The progress of the reaction was monitored by thin layer chromatography (TLC) and after the starting material of formula 3 was completely consumed, 20 mL of saturated aqueous sodium bicarbonate (NaHCO 3 ) was added. The reaction mixture was transferred to a separatory funnel and extracted with chloroform (3 ⁇ 50 mL).
  • TLC thin layer chromatography

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Abstract

L'invention concerne : un nouveau composé de dicétopipérazine pour la synthèse rapide et facile de divers polypeptides ; et son procédé de fabrication. Le composé de dicétopipérazine est représenté par la formule générale (1). (Dans la formule, R1, R2, R3, R4 et R5 sont chacun indépendamment un atome d'hydrogène, un groupe hydrocarboné substitué ou non substitué, ou un groupe hétérocyclique substitué ou non substitué. R1 et R2, R1 et R5, R2 et R5, et/ou R3 et R4 sont chacun éventuellement liés pour former un cycle. PGE représente un groupe protecteur attracteur d'électrons.)
PCT/JP2023/036352 2022-10-07 2023-10-05 Synthèse de polypeptides à l'aide d'un composé de dicétopipérazine WO2024075813A1 (fr)

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